Pyrazino-pyridazine derivatives as ligands for gaba receptors

ABSTRACT

A class of pyrazino[2,3-d]pyridazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 5-position, a substituted alkoxy moiety at the 3-position, and a range of substituents at the 2-position, are selective ligands for GABA A  receptors, in particular having high affinity for the α2 and/or α3 and/or α5 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of adverse conditions of the central nervous system, including anxiety, ceonvulsions and cognitive disorders.

[0001] The present invention relates to a class of substitutedpyrazino-pyridazine derivatives and to their use in therapy. Moreparticularly, this invention is concerned with substitutedpyrazino[2,3-d]pyridazine derivatives which are ligands for GABA_(A)receptors and are therefore useful in the therapy of deleterious mentalstates.

[0002] Receptors for the major inhibitory neurotransmitter,gamma-aminobutyric acid (GABA), are divided into two main classes: (1)GABA_(A) receptors, which are members of the ligand-gated ion channelsuperfamily; and (2) GABA_(B) receptors, which may be members of theG-protein linked receptor superfamily. Since the first cDNAs encodingindividual GABA_(A) receptor subunits were cloned the number of knownmembers of the mammalian family has grown to include at least six a,subunits, four S subunits, three γ subunits, one δ subunit, one εsubunit and two ρ subunits.

[0003] Although knowledge of the diversity of the GABA_(A) receptor genefamily represents a huge step forward in our understanding of thisligand-gated ion channel, insight into the extent of subtype diversityis still at an early stage. It has been indicated that an α subunit, a βsubunit and a γ subunit constitute the minimum requirement for forming afully functional GABA_(A) receptor expressed by transiently transfectingcDNAs into cells. As indicated above, δ, ε and ρ subunits also exist,but are present only to a minor extent in GABA_(A) receptor populations.

[0004] Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof seventeen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangement ofsubunits around the ion channel had no constraints (i.e. there could be120 possible variants for a receptor composed of five differentsubunits).

[0005] Receptor subtype assemblies which do exist include, amongst manyothers, α1β2γ2, α2β2/3γ2, α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βδ andα4βδ. Subtype assemblies containing an α1 subunit are present in mostareas of the brain and are thought to account for over 40% of GABA_(A)receptors in the rat. Subtype assemblies containing α2 and α3 subunitsrespectively are thought to account for about 25% and 17% of GABA_(A)receptors in the rat. Subtype assemblies containing an α5 subunit areexpressed predominantly in the hippocampus and cortex and are thought torepresent about 4% of GABA_(A) receptors in the rat.

[0006] A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine (BZ) binding site. The BZ binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which anxiolytic drugs such as diazepam and temazepam exerttheir effect. Before the cloning of the GABA_(A) receptor gene family,the benzodiazepine binding site was historically subdivided into twosubtypes, BZ1 and BZ2, on the basis of radioligand binding studies. TheBZ1 subtype has been shown to be pharmacologically equivalent to aGABA_(A) receptor comprising the α1 subunit in combination with a βsubunit and γ2. This is the most abundant GABA_(A) receptor subtype, andis believed to represent almost half of all GABA_(A) receptors in thebrain.

[0007] Two other major populations are the α2βγ2 and α3βγ2/3 subtypes.Together these constitute approximately a further 35% of the totalGABA_(A) receptor repertoire. Pharmacologically this combination appearsto be equivalent to the BZ2 subtype as defined previously by radioligandbinding, although the BZ2 subtype may also include certain α5-containingsubtype assemblies. The physiological role of these subtypes hashitherto been unclear because no sufficiently selective agonists orantagonists were known.

[0008] It is now believed that agents acting as BZ agonists at α1βγ2,α2γγ2 or α3βγ2 subtypes will possess desirable anxiolytic properties.Compounds which are modulators of the benzodiazepine binding site of theGABA_(A) receptor by acting as BZ agonists are referred to hereinafteras “GABA_(A) receptor agonists”. The α1-selective GABA_(A) receptoragonists alpidem and zolpidem are clinically prescribed as hypnoticagents, suggesting that at least some of the sedation associated withknown anxiolytic drugs which act at the BZ1 binding site is mediatedthrough GABA_(A) receptors containing the α1 subunit. Accordingly, it isconsidered that GABA_(A) receptor agonists which interact morefavourably with the α2 and/or α3 subunit than with α1 will be effectivein the treatment of anxiety with a reduced propensity to cause sedationMoreover, agents which are inverse agonists of the α5 subunit are likelyto be beneficial in enhancing cognition, for example in subjectssuffering from dementing conditions such as Alzheimer's disease. Also,agents which are antagonists or inverse agonists at α1 might be employedto reverse sedation or hypnosis caused by α1 agonists.

[0009] The compounds of the present invention, being selective ligandsfor GABA_(A) receptors, are therefore of use in the treatment and/orprevention of a variety of disorders of the central nervous system. Suchdisorders include anxiety disorders, such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,animal and other phobias including social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic and acute stressdisorder, and generalized or substance-induced anxiety disorder;neuroses; convulsions; migraine; depressive or bipolar disorders, forexample single-episode or recurrent major depressive disorder, dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder; psychotic disorders including schizophrenia; neurodegenerationarising from cerebral ischemia; attention deficit hyperactivitydisorder; and disorders of circadian rhythm, e.g. in subjects sufferingfrom the effects of jet lag or shift work.

[0010] Further disorders for which selective ligands for GABA_(A)receptors may be of benefit include pain and nociception; emesis,including acute, delayed and anticipatory emesis, in particular emesisinduced by chemotherapy or radiation, as well as post-operative nauseaand vomiting; eating disorders including anorexia nervosa and bulimianervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. inparaplegic patients; and hearing loss. Selective ligands for GABA_(A)receptors may be beneficial in enhancing cognition, for example insubjects suffering from dementing conditions such as Alzheimer'sdisease; and may also be effective as pre-medication prior toanaesthesia or minor procedures such as endoscopy, including gastricendoscopy.

[0011] The present invention provides a class of pyrazino-pyridazinederivatives which possess desirable binding properties at variousGABA_(A) receptor subtypes. The compounds in accordance with the presentinvention have good affinity as ligands for the α2 and/or α3 and/or α5subunit of the human GABA_(A) receptor. The compounds of this inventionmay interact more favourably with the α2 and/or α3 subunit than with theα1 subunit; and/or may interact more favourably with the α5 subunit thanwith the α1 subunit.

[0012] The compounds of the present invention are GABA_(A) receptorsubtype ligands having a binding affinity (K_(i)) for the α2 and/or α3and/or α5 subunit of 100 nM or less, typically of 50 nM or less, andideally of 10 nM or less. The compounds in accordance with thisinvention may possess at least a 2-fold, suitably at least a 5-fold, andadvantageously at least a 10-fold, selective affinity for the α2 and/orα3 and/or α5 subunit relative to the α1 subunit. However, compoundswhich are not selective in terms of their binding affinity for the α2and/or α3 and/or α5 subunit relative to the α1 subunit are alsoencompassed within the scope of the present invention; such compoundswill desirably exhibit functional selectivity in terms of zero or weak(positive or negative) efficacy at the α1 subunit and (i) a full orpartial agonist profile at the α2 and/or α3 subunit, and/or (ii) aninverse agonist profile at the α5 subunit.

[0013] The present invention provides a compound of formula I, or a saltor prodrug thereof:

[0014] wherein

[0015] Z represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₆₋₈bicycloalkyl, aryl, C₃₋₄ heterocycloalkyl, heteroaryl ordi(C₁₋₆)alkylamino, any of which groups may be optionally substituted;

[0016] R¹ represents C₃₋₇ cycloalkyl, phenyl, furyl, thienyl orpyridinyl, any of which groups may be optionally substituted; and

[0017] R² represents C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted.

[0018] The groups Z, R¹ and R² may be unsubstituted, or substituted byone or more, suitably by one or two, substituents. In general, thegroups Z, R¹ and R² will be unsubstituted or monosubstituted. Examplesof optional substituents on the groups Z, R¹ and R² include C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, pyridyl(C₁₋₆)alkyl, halogen, halo(C₁₋₆)alkyl, cyano,cyano(C₁₋₆)alkyl, hydroxy, hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl(C₁₋₆)alkoxy, C₃₋₇ cycloalkoxy, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl,N-(C₁₋₆)alkylpiperidinyl, pyrrolidinyl(C₁₋₆)alkyl,piperazinyl(C₁₋₆)alkyl, morpholinyl(C₁₋₆)alkyl,di(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl and imidazolyl(C₁₋₆)alkyl.Representative substituents include C₁₋₆ alkyl, aryl(C₁₋₆)alkyl,halogen, cyano, hydroxy, hydroxymethyl, C₁₋₆ alkoxy and C₃₋₇cycloalkyl(C₁₋₆)alkoxy. Particular substituents include methyl, ethyland fluoro.

[0019] As used herein, the expression “C₁₋₆ alkyl” includes methyl andethyl groups, and straight-chained or branched propyl, butyl, pentyl andhexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,isopropyl, sec-butyl, tert-butyl and 1,1-dimethylpropyl. Derivedexpressions such as “C₁₋₆ alkoxy” are to be construed accordingly.

[0020] Typical C₃₋₇ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

[0021] The expression “C₃₋₇ cycloalkyl(C₁₋₆)alkyl” as used hereinincludes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

[0022] Typical C₄₋₇ cycloalkenyl groups include cyclobutenyl,cyclopentenyl and cyclohexenyl.

[0023] Typical C₆₋₈ bicycloalkyl groups include bicyclo[2.1.1]hexyl andbicyclo [2.2.1]heptyl.

[0024] Typical aryl groups include phenyl and naphthyl, preferablyphenyl.

[0025] The expression “aryl(C₁₋₆)alkyl” as used herein includes benzyl,phenylethyl, phenylpropyl and naphthylmethyl.

[0026] Suitable heterocycloalkyl groups include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinylgroups.

[0027] Suitable heteroaryl groups include pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl,benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl,pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl andtetrazolyl groups.

[0028] The expression “heteroaryl(C₁₋₆)alkyl” as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

[0029] The term “halogen” as used herein includes fluorine, chlorine,bromine and iodine, especially fluorine or chlorine.

[0030] For use in medicine, the salts of the compounds of formula I willbe pharmaceutically acceptable salts. Other salts may, however, beuseful in the preparation of the compounds according to the invention orof their pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

[0031] The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

[0032] Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

[0033] Examples of suitable values for the substituent Z include methyl,ethyl, isopropyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl,cyclopropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl,cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl,bicyclo[2.1.1]hex-1-yl, bicyclo[2.2.1]hept-1-yl, phenyl, pyrrolidinyl,methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyridinyl, furyl, thienyl, chloro-thienyl and diethylamino.

[0034] Specific values of Z include sec-butyl, tert-butyl, cyclopropyl,cyclohexyl, phenyl, furyl and thienyl.

[0035] Examples of typical optional substituents on the group R¹ includemethyl, fluoro and methoxy, especially fluoro.

[0036] Representative values of R¹ include cyclopropyl, phenyl,methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl,thienyl, methyl-thienyl and pyridinyl. More particularly, R¹ mayrepresent unsubstituted, monosubstituted or disubstituted phenyl. Mostparticularly, R¹ represents phenyl, fluorophenyl or difluorophenyl,especially phenyl.

[0037] Suitably, R² represents aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl,either of which groups may be optionally substituted.

[0038] Suitable values for the substituent R² in the compounds accordingto the invention include cyclohexylmethyl, benzyl, pyrazolylmethyl,isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl,tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl,pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl andquinoxalinylmethyl, any of which groups may be optionally substituted byone or more substituents.

[0039] Suitably, R² represents an optionally substituted triazolylmethylgroup.

[0040] Examples of suitable optional substituents on the group R²include C₁₋₆ alkyl, aryl(C₁₋₆)alkyl, pyridyl(C₁₋₆)alkyl, halogen,halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, hydroxymethyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl(C₁₋₆)alkoxy, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl,N-(C₁₋₆)alkylpiperidinyl, pyrrolidinyl(C₁₋₆)alkyl,piperazinyl(C₁₋₆)alkyl, morpholinyl(C₁₋₆)alkyl anddi(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl, especially C₁₋₆ alkyl.

[0041] Specific illustrations of particular substituents on the group R²include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro,chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy,cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl,dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl,piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl,especially methyl or ethyl.

[0042] Representative values of R² includehydroxymethyl-cyclohexylmethyl, cyanobenzyl, hydroxymethyl-benzyl,pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl,thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl,methyl-thiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl,ethyl-imidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl,methyl-oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl,ethyl-triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl,pyridinylmethyl-triazolylmethyl, cyanomethyl-triazolylmethyl,dimethylaminomethyl-triazolylmethyl, aminoethyl-triazolylmethyl,dimethylaminoethyl-triazolylmethyl,dimethylaminocarbonylmethyl-triazolylmethyl,N-methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl,piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl,methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl,dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl,cyclopropylmethoxy-pyridinylmethyl, pyridazinylmethyl,chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,quinolinylmethyl, isoquinolinylnethyl and quinoxalinylmethyl.

[0043] Favoured values of R² include methyl-triazolylmethyl anethyl-triazolylmethyl.

[0044] A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof:

[0045] wherein

[0046] Z and R¹ are as defined with reference to formula I above;

[0047] m is 1 or 2, preferably 1; and

[0048] R¹² represents aryl or heteroaryl, either of which groups may beoptionally substituted.

[0049] Suitably, R¹² represents phenyl, pyrazolyl, isoxazolyl,thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl,isoquinolinyl or quinoxalinyl, any of which groups may be optionallysubstituted by one or more substituents.

[0050] A particular value of R¹² is optionally substituted triazolyl.

[0051] Examples of typical substituents on the group R¹² include C₁₋₆alkyl, aryl(C₁₋₆)alkyl, pyridyl(C₁₋₆)alkyl, halogen, cyano,cyano(C₁₋₆)alkyl, hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl(C₁₋₆)alkoxy, di(C₁₋₆)alkylamino(C₁₋₆)alkyl, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl, N-(C₁₋₆)alkylpiperidinyl,pyrrolidinyl(C₁₋₆)alkyl, piperazinyl(C₁₋₆)alkyl andmorpholinyl(C₁₋₆)alkyl, especially C₁₋₆ alkyl.

[0052] Illustrative values of specific substituents on the group R¹²include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano,cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy,dimethylaminomethyl, aminoethyl, dimethylaminoethyl,dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl,piperazinylethyl and morpholinylmethyl, especially methyl or ethyl.

[0053] Particular values of R¹² include cyanophenyl,hydroxymethyl-phenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl,thiazolyl, methyl-thiazolyl, ethyl-thiazolyl, imidazolyl,methyl-imidazolyl, ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl,methyl-oxadiazolyl, triazolyl, methyl-triazolyl, ethyl-triazolyl,propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl,cyanomethyl-triazolyl, dimethylaminomethyl-triazolyl,aminoethyl-triazolyl, dimethylaminoethyl-triazolyl,dimethylaminocarbonylmethyl-triazolyl, N-methylpiperidinyl-triazolyl,pyrrolidinylethyl-triazolyl, piperazinylethyl-triazolyl,morpholinylethyl-triazolyl, methyl-tetrazolyl, pyridinyl,methyl-pyridinyl, dimethyl-pyridinyl, ethoxy-pyridinyl,cyclopropylmethoxy-pyridinyl, pyridazinyl, chloro-pyridazinyl,pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.

[0054] Favoured values of R¹² include methyl-triazolyl andethyl-triazolyl.

[0055] A particular subset of the compounds of formula IIA above isrepresented by the compounds of formula IIB, and pharmaceuticallyacceptable salts thereof:

[0056] wherein

[0057] R¹ is as defined with reference to formula I above;

[0058] Q represents the residue of a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, furyl or thienyl ring;

[0059] R³ represents hydrogen, methyl or fluoro; and

[0060] R⁴ represents methyl or ethyl.

[0061] In relation to formula IIB above, R¹ suitably represents phenyl,fluorophenyl or difluorophenyl, especially phenyl.

[0062] In a particular embodiment, Q suitably represents the residue ofa cyclobutyl ring. In another embodiment, Q represents the residue of acyclopropyl or cyclohexyl ring. In a further embodiment, Q representsthe residue of a phenyl, furyl or thienyl ring.

[0063] Suitably, R³ represents hydrogen.

[0064] In a particular embodiment R⁴ suitably represents methyl. Inanother embodiment, R⁴ represents ethyl.

[0065] Specific compounds within the scope of the present inventioninclude:

[0066]2-cyclohexyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;

[0067]2-sec-butyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3d]pyridazine;

[0068]2-cyclopropyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;

[0069]3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-2-(furan-2-yl)-5-phenylpyrazino[2,3-d]pyridazine;

[0070]2-tert-butyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;

[0071]2-tert-butyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;

[0072]2,5-diphenyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine;

[0073]2,5-diphenyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine;

[0074]3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenyl-2-(2-thienyl)-pyrazino[2,3-d]pyridazine;

[0075] and salts and prodrugs thereof.

[0076] Also provided by the present invention is a method for thetreatment and/or prevention of anxiety which comprises administering toa patient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable saltthereof.

[0077] Further provided by the present invention is a method for thetreatment and/or prevention of convulsions (e.g. in a patient sufferingfrom epilepsy or a related disorder) which comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable salt thereofThe compounds according to the present invention may exhibit anxiolyticactivity, as may be demonstrated by a positive response in the elevatedplus maze and conditioned suppression of drinking tests (cf. Dawson etal., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds ofthe invention are likely to be substantially non-sedating, as may beconfirmed by an appropriate result obtained from the responsesensitivity (chain-pulling) test (cf. Bayley et al., J.Psychopharmacol., 1996, 10, 206-213).

[0078] The compounds according to the present invention may also exhibitanticonvulsant activity. This can be demonstrated by the ability toblock pentylenetetrazole-induced seizures in rats and mice, following aprotocol analogous to that described by Bristow et al. in J. Pharmacol.Exp. Ther., 1996, 279, 492-501.

[0079] In another aspect, the present invention provides a method forthe treatment and/or prevention of cognitive disorders, includingdementing conditions such as Alzheimer's disease, which comprisesadministering to a patient in need of such treatment an effective amountof a compound of formula I as defined above or a pharmaceuticallyacceptable salt thereof.

[0080] Cognition enhancement can be shown by testing the compounds inthe Morris watermaze as reported by McNamara and Skelton, Psychobiology,21, 101-108.

[0081] Cognitive disorders for which the compounds of the presentinvention may be of benefit include delirium, dementia, amnesticdisorders, and cognition deficits, including age-related memorydeficits, due to traumatic injury, stroke, Parkinson's disease and DownSyndrome. Any of these conditions may be attributable to substance abuseor withdrawal. Examples of dementia include dementia of the Alzheimer'stype with early or late onset, and vascular dementia, any of which maybe uncomplicated or accompanied by delirium, delusions or depressedmood; and dementia due to HIV disease, head trauma, Parkinson's diseaseor Creutzfeld-Jakob disease.

[0082] In order to elicit their behavioural effects, the compounds ofthe invention will ideally be brain-penetrant; in other words, thesecompounds will be capable of crossing the so-called “blood-brainbarrier”. Preferably, the compounds of the invention will be capable ofexerting their beneficial therapeutic action following administration bythe oral route.

[0083] The invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

[0084] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0085] In the treatment of neurological disorders, a suitable dosagelevel is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100mg/kg per day, and especially about 0.05 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day.

[0086] The compounds of formula I as defined above may be prepared by aprocess which comprises reacting a compound of formula III (or its2-hydroxypyrazino[2,3-d]pyridazine tautomer) with a compound of formulaIV:

R²-L¹  (IV)

[0087] wherein Z, R¹ and R² are as defined above, and L¹ represents asuitable leaving group.

[0088] The leaving group L¹ is suitably the moiety formed when a hydroxygroup reacts with triphenylphosphine in the presence ofdiethylazodicarboxylate.

[0089] The reaction between compounds III and IV is convenientlyeffected by stirring the reactants in a suitable solvent, typicallydichloromethane.

[0090] The precursors to the intermeidates of formula IV above, where L¹is hydroxy, may be prepared by the procedures described in WO 98/04559,or by methods analogous thereto.

[0091] Where they are not commercially available, the starting materialsof formula III may be prepared by methods analogous to those describedin the accompanying Examples, or by standard methods well known from theart.

[0092] It will be understood that any compound of formula I initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula I bytechniques known from the art. For example, a compound of formula Iinitially obtained wherein R² is unsubstituted may be converted into acorresponding compound wherein R² is substituted, typically by standardalkylation procedures, for example by treatment with a haloalkylderivative in the presence of sodium hydride and N,N-dimethylformamide,or with a hydroxyalkyl derivative in the presence of triphenylphosphineand diethyl azodicarboxylate. Furthermore, a compound of formula Iinitially obtained wherein the R² substituent is substituted by ahalogen atom, e.g. chloro, may be converted into the correspondingcompound wherein the R² substituent is substituted by adi(C₁₋₆)alkylamino moiety by treatment with the appropriatedi(C₁₋₆)alkylamine, typically with heating in a solvent such as1,4-dioxane in a sealed tube.

[0093] Where the above-described processes for the preparation of thecompounds according to the invention give rise to mixtures ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The novel compounds may be preparedin racemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

[0094] During any of the above synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[0095] The following Examples illustrate the preparation of compoundsaccording to the invention.

[0096] The compounds in accordance with this invention potently inhibitthe binding of [³H]-flumazenil to the benzodiazepine binding site ofhuman GABA_(A) receptors containing the α2 or α3 or α5 subunit stablyexpressed in Ltk⁻ cells.

[0097] The compounds of the accompanying Examples have all been found topossess a K_(i) value for displacement of [³H]-flumazenil from the α2and/or α3 and/or α5 subunit of the human GABA_(A) receptor of 100 nM orless.

EXAMPLE 1

[0098]2-Cyclohexyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pridazine

[0099] a) 4-Amino-6-phenyl-3(2H)-pyridazinone

[0100] To acetophenone (250 g, 2 mol) was added glyoxylic acid (61.37 g,0.66 mol) and the mixture heated at 105° C. for 3 hours. After coolingto room temperature the reaction was diluted with water followed byconcentrated (0.880) aqueous ammonia (53 ml). The unreacted acetophenonewas extracted into dichloromethane and recovered. The ammoniacalsolution was stirred with hydrazine hydrate (33 ml) and heated at refluxfor two hours. The solid which precipitated on cooling was collected byfiltration then added to hydrazine hydrate (550 ml) and the mixtureheated at reflux for 12 hours. The solid was collected by filtration,washed with water followed by cold acetonitrile and dried under vacuumto give a white solid (73.9 g; 59.3%). ¹H NMR (400 MIz, DMSO-d₆) δ 12.66(1H, bs), 8.91 (1H, s), 7.72 (2H, m), 7.41 (1H, m), 6.73 (1H, s), 6.43(2H, bs); m/e (ES⁺) 188 [MH]⁺.

[0101] b) 4-Amino-5-bromo-6-phenyl-3(2H)-pyridazinone

[0102] 4-Amino-6-phenyl-3(2H)-pyridazinone (prepared by the method ofExample 1a), or according to McKillop et al., Heterocycles, 1989, 29(6),1077) (4.69 g, 25 mmol) and N-bromosuccinimide (4.50 g, 25.3 mmol),suspended in dry acetonitrile (135 ml), was heated at reflux under anitrogen atmosphere for 6 hours, then allowed to stand at roomtemperature for 18 hours. The solid was collected by filtration, washedwith ethyl acetate (40 ml) and diethyl ether (40 ml), and dried in vacuoat 60° C., to afford the title compound, 6.25 g (94%), as a colourlesssolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.93 (1H, s), 7.43 (5H, m), 6.69(2H, br s); m/e (ES⁺) 266/268 [MH]⁺.

[0103] c)4-[Bis(tert-butoxycarbonyl)amido]-5-bromo-6-phenyl-3(2H)-pyridazinone

[0104] To the product of Example 1b) (25 g, 94 mmol), and4-dimethylaminopyridine (0.44 g), suspended in dry N,N-dimethylformamide(250 ml), was added, with stirring, di-tert-butyl dicarbonate (62 g)portionwise. On completion of addition, the mixture was stirred anadditional 2 hours at room temperature, then most of the solvent wasstripped at reduced pressure. The residue was partitioned between ethylacetate and water, and the organic phase separated and washed withwater, evaporated, and the residue azeotroped with toluene at reducedpressure to afford a yellow foam. This was dissolved in warm methanol(500 ml), silica gel (flash chromatography grade, 80 g) added, and themixture was stirred at room temperature for 36 hours. The reaction wasthen diluted with dichloromethane (1.5 l) and the silica removed byfiltration. The filtrate was evaporated at reduced pressure, and theresidue crystallised from diethyl ether and isohexane and dried in vacuoat 40° C., to afford the title compound, 31.28 g (71%), as a colourlesssolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.79 (1H, s), 7.49 (5H, m), 1.40(18H, s); m/e (ES⁺) 310/312 [MH-Boc-(CH₃)₂CCH₂)]⁺, 266/268 [MH-2Boc]⁺.

[0105] d)5-Azido-4-[bis(tert-butoxcyarbonyl)amidol-6-phenyl-3(2H)-pyridazinone

[0106] To the product of Example Ic) (31 g, 67 mmol) in dryN,N-dimethylformamide (100 ml) was added, with stirring,tetramethylguanidinium azide (12 g, 1.1 equivalents), and the solutionwas then heated at 70° C. for 20 hours (behind a perspex blast screen).The reaction mixture was cooled to room temperature then most of thesolvent was stripped at reduced pressure. The residue was diluted withethyl acetate (150 ml) and washed with water (2×100 ml), then brine (50ml). The organic phase was evaporated, and the residue was crystallisedfrom diethyl ether/isohexane and dried in vacuo at 30° C., to afford thetitle compound, 24.7 g (86%), as a pale yellow solid, m.p. 149-150° C.dec. ¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (1H, s), 7.58 (2H, m), 7.49 (3H,m), 1.43 (18H, s).

[0107] e)5-Amino-4-[bis(tert-butoxycarbonyl)amido]-6-phenyl-3(2H)-pyridazinone

[0108] To the product of Example 1d) (24.7 g, 57.6 mmol), indichloromethane (100 ml) and ethanol (400 ml), was added under nitrogen10% palladium on carbon (2.5 g). The mixture was then hydrogenated underan atmosphere of hydrogen gas, with stirring, for 18 hours. The catalystwas removed by filtration, and the filter cake washed well with 10%ethanol in dichloromethane. Most of the solvent was stripped from thecombined filtrates at reduced pressure. The residue was crystallisedfrom ethanol and dried in vacuo at 40° C., to afford the title compound,23 g (99%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (1H, s), 7.48 (3H, m),7.43 (2H, m), 5.95 (2H, br s), 1.38 (18H, s); m/e (ES⁺) 403 MH]⁺, 247[MH-Boc-(CH₃)₂CCH₂)]⁺.

[0109] f) 4,5-Diamino-6-phenyl-3(2H)-pyridazinone Hydrochloride

[0110] To the product of Example 1e) (23 g, 57 mmol) was added asaturated solution of hydrogen chloride in methanol (500 ml), and theresulting solution allowed to stand for 18 hours under a nitrogenatmosphere. The solvent was stripped at reduced pressure, and theresidue azeotroped with toluene to afford a hydrochloride salt ofunknown stoichiometry as a yellow foam, which was dried in vacuo at 40°C., and used without further purification. m/e (ES⁺) 203 [MH]⁺.

[0111] g) N-(5-Amino-6-phenyl-3(2H)-pyridazin-4-yl) DiethylPhosphoramidate

[0112] To the product of Example 1f) (˜57 mmol) was added phosphorusoxychloride (150 ml) and N,N-dimethylaniline (30 ml). The mixture wasthen heated at reflux, with stirring, for 3 hours. The resultingsolution was cooled to room temperature, and the excess phosphorusoxychloride was removed by evaporation at reduced pressure. The residuewas cooled in an ice bath, and quenched by cautious addition of ethanol(250 ml). The resulting solution was transferred to a 2 l Parr flask,and ethanol (100 ml) was added. 10% Palladium on carbon (5 g) wasintroduced under a nitrogen atmosphere. The mixture was thenhydrogenated at 30 psi pressure of hydrogen gas for 24 hours. Thecatalyst was removed by filtration, fresh 10% palladium on carbon (5 g)was introduced under a nitrogen atmosphere, and the mixture was thenhydrogenated at 30 psi pressure of hydrogen gas for 72 hours. Thecatalyst was removed by filtration, and the filtrate was evaporated atreduced pressure. The residue was neutralised by addition of aqueousammonia, and extracted with ethyl acetate. The organic extracts wereevaporated at reduced pressure, and the residue was triturated withdiethyl ether and decanted to wash out most of the N,N-dimethylaniline.The residual solid was crystallised from ethyl acetate and diethylether, and dried in vacuo at 40° C., to afford the title compound, 7.5 g(40%), as a pale yellow solid. ¹H NMR (360 MHz, CDCl₃) δ 8.75 (1H, s),7.73 (1H, br m), 7.63 (21, m), 7.49 (3H, m), 5.26 (2H, br s), 4.17 (41,m), 1.35 (6H, m); nm/e (ES⁺) 323 [MH]⁺.

[0113] h) 3-Cyclohexyl-8-phenyl-1H-pyrazino[2,3-d]pyridazin-2-one

[0114] To the product of Example 1g) (0.400 g, 1.24 mmol) indichloromethane (4 ml) and tetrahydrofuran (4 ml) was addedcyclohexylglyoxylic acid (0.388 g, 2.4 mmol) and1,3-dicyclohexylcarbodiimide (0.770 g, 3.7 mmol) and the mixture stirredfor 18 hours. The reaction was diluted with 10% methanol indichloromethane and adsorbed onto silica gel. The crude product waspurified by flash chromatography (silica gel, eluent ethyl acetate) togive the product as a cream coloured solid (0.223 g; 58%). ¹H NMR (400MHz, DMSO-d₆) δ 12.80 (1H, bs), 9.49 (1H, s), 8.11 (2H, m), 7.98 (1H,s), 7.57 (31, m), 6.87 (1H, m), 3.21 (1H, m), 2.00 (2H, m), 1.85 (2H,m), 1.60 (3H, m), 1.36 (3H, m); m/e (ES⁺) 307 [MH]⁺.

[0115] i)2-Cyclohexyl-3-(2-ethyl-2H-[12.4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine

[0116] To a solution of the product of Example 1h) (0.200 g, 0.65 mmol),triphenylphosplhine (0.275 g, 0.98 mmol) and(2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (prepared as described in WO98/50385) (0.130 g, 0.98 mmol), at 0° C., was addeddiethylazodicarboxylate (154 μl, 0.98 mmol) dropwise with stirring. Thereaction mixture was then stirred at room temperature for 18 hours. Thesolvent was removed under reduced pressure and the crude productpurified by flash chromatography (silica gel, eluent ethyl acetate). Thesolid obtained was recrystallised from dichloromethane/ethylacetate/isohexane to yield the title compound as a cream coloured solid(0.129 g; 47%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (1H, s), 8.11 (2H, m),7.98 (1H, s), 7.57 (3H, m), 6.87 (1H, m), 5.74 (1H, s), 4.18 (2H, q, J7.2 Hz), 3.21 (1H, m), 2.00 (2H, m), 1.85 (2H, m), 1.60 (3H, m), 1.36(3H, m), 1.30 (3H, t, J 7.3 Hz); m/e (ES⁺) 416 [MH]⁺; Anal. found: C,66.44; H, 6.00; N, 23.44%. C₂₃H₂₅N₇O requires: C, 66.49; H, 6.06; N,23.60%.

EXAMPLE 2

[0117]2-sec-Butyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine

[0118] a) 3-sec-Butyl-8-phenyl-1H-pyrazino[2,3-d]pyridazin-2-one

[0119] By an entirely analogous method to that used for Example 1h), bututilizing sec-butylglyoxylic acid instead of cyclohexylglyoxylic acid,the title product was prepared as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.03 (1H, bs), 9.37 (1H, s), 7.72 (2H, m), 7.56 (3H, m),1.74 (1H, m), 1.22 (2H, m), 1.13 (3H, d), 0.97 (3H, t, J 7.3 Hz); m/e(ES⁺) 281 [MH]⁺.

[0120] b)2-sec-Butyl-3-(2-ethyl-2H-[1.2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine

[0121] By reaction of the product of Example 2a) according to the methodof Example 1i), the title compound was prepared as a cream colouredsolid. ¹H NMR (400 MHz, DMSO₆) δ 9.71 (1H, s), 8.15 (2H, m), 7.99 (1H,s), 7.58 (3H, m), 5.73 (1H, m), 4.19 (2H, q, J 7.2 Hz), 3.35 (1H, m),1.94 (1H, m), 1.64 (1H, m), 1.31 (6H, m), 0.87 (3H, t, J 7.3 Hz); m/e(ES⁺) 390 [MH]⁺; Anal. found: C, 64.04; H, 5.91; N, 24.62%.C₂₁H₂₃N₇O.(0.2H₂O) requires: C, 64.17; H, 6.00; N, 24.94%.

EXAMPLE 3

[0122]2-Cyclopropyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[23-d]pyridazine

[0123] a) 3-Cyclopropyl-8-phenyl-1H-pyrazino[2.3-d]pyridazin-2-one

[0124] By an entirely analogous method to that used for Example 1h), bututilizing cyclopropylglyoxylic acid instead of cyclohexylglyoxylic acid,the title product was prepared as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.43 (1H, bs), 9.37 (1H, s), 7.72 (2H, m), 7.56 (3H, m),2.61 (1H, m), 1.31 (4H, m); m/e (ES⁺) 265 [MH]⁺.

[0125] b)2-Cyclopropyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine

[0126] By reaction of the product of Example 3a) according to the methodof Example 1i), the title compound was prepared as a cream solid. ¹H NMR(360 MHz, DMSO-d₆) δ 9.57 (1H, s), 8.15 (2H, m), 8.00 (1H, s), 7.57 (3H,m), 5.74 (1H, s), 4.21 (2H, q, J 7.2 Hz), 2.61 (1H, m), 1.31 (7H, m);m/e (ES⁺) 374 [MH]⁺. Anal. found: C, 63.86; H, 4.97; N, 25.88%.C₂₀H₁₉N₇O.(0.1H₂O) requires: C, 64.02; H, 5.16; N, 26.13%.

EXAMPLE 4

[0127]3-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-2-(furan-2-yl)-5-phenylpyrazino[2,3-d]pyridazine

[0128] a) 3-(Furan-2-yl)-8-phenyl-1H-pyrazino[2.3-d]pyridazin-2-one

[0129] By an entirely analogous method to that used for Example 1h, bututilizing (2-furyl)glyoxylic acid instead of cyclohexylglyoxylic acid,the title product was prepared as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.9 (1H, bs), 9.45 (1H, s), 8.13 (1H, s), 7.96 (1H, d, J 3.0Hz), 7.77 (2H, bs), 7.57 (3H, bs), 6.81 (1H, bs); m/e (ES⁺) 291 [MH]⁺.

[0130] b)3-(2-Ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-2-(furan-2-yl)-5-phenylpyrazino[2,3-d]pyridazine

[0131] By reaction of the product of Example 4a according to the methodof Example 1i, the title compound was prepared as a pale yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (1H, s), 8.19 (3H, m), 8.04 (1H, s),7.67 (1H, d, J 3.4 Hz), 7.59 (3H, m), 6.87 (1H, m), 5.85 (1H, s), 4.20(2H, q, J 7.2 Hz), 1.30 (3H, t, J 7.3 Hz); m/e (ES⁺) 400 [MH]⁺; Anal.found: C, 62.68; H, 4.07; N, 24.17%. C₂₁H₁₇N₇O₂.(0.1H₂O) requires: C,62.86; H, 4.32; N, 24.43%.

EXAMPLE 5

[0132]2-tert-Butyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine

[0133] a) 3-tert-Butyl-8-phenyl-1H-pyrazino[2,3-d]pridazin-2-one

[0134] By an entirely analogous method to that used for Example 1h, bututilizing tert-butylglyoxylic acid instead of cyclohexylglyoxylic acid,the title product was obtained. ¹H NMR (360 MHz, CDCl₃) δ 9.72 (1H, bs),9.38 (1H, s), 7.68 (2H, m), 7.55 (3H, m), 1.44 (9H, s).

[0135] b)2-tert-Butyl-3-(2-etlhyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazinol[2,3-d]pyridazine

[0136] By reaction of the product of Example 5a) according to the methodof Example 1i), the title compound was prepared. Recrystallisation fromethyl acetate/diethyl ether afforded colourless needles. ¹H NMR (400MHz, DMSO-d₆) δ 9.69 (1H, s), 8.14 (2H, m), 8.00 (1H, s), 7.58 (3H, m),5.77 (2H, s), 4.15 (2H, q, J 7.2 Hz), 1.47 (9H, s), 1.29 (3H, t, J 7.2Hz); m/e (ES⁺) 390 [MH]⁺; Anal. found: C, 64.31; H, 5.91; N, 25.09%.C₂₁H₂₃N₇O.(0.125H₂O) requires: C, 64.39; H, 5.98; N, 25.03%.

EXAMPLE 6

[0137]2-tert-Butyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pridazine

[0138] By reaction of the product of Example 5a) according to the methodof Example 1i), but utilizing (1-methyl-1H-[1,2,4]triazol-3-yl)methanol(prepared as described in WO 98/04559), the title compound was prepared.Recrystallisation from dichloromethane/diethyl ether/isohexane affordedpale yellow needles. ¹H NMR (400 MHz, CDCl₃) δ 9.64 (1H, s), 8.26 (2H,m), 8.05 (1H, s), 7.53 (3H, m), 5.64 (2H, s), 3.94 (3H, s), 1.52 (9H,s); m/e (ES⁺) 376 [MH]⁺.

EXAMPLE 7

[0139]2,5-Diphenyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine

[0140] a) 3,8-Diphenyl-1H-pyrazino[2,3-d]pyridazin-2-one

[0141] By an entirely analogous method to that used for Example 1h), bututilizing phenylglyoxylic acid instead of cyclohexylglyoxylic acid, thetitle product was obtained. ¹H NMR (360 MHz, DMSO-d₆) δ 12.70 (1H, bs),9.46 (1H, s), 8.33 (2H, m), 7.78 (2H, m), 7.57 (6H, m); m/e (ES⁺) 301[MH]⁺.

[0142] b)2,5-Diphenyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine

[0143] By reaction of the product of Example 7a) according to the methodof Example 1i) the title compound was prepared. Recrystallisation fromdichloromethane/diethyl ether/isohexane afforded a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.79 (1H, s), 8.18 (2H, m), 8.13 (2H, m), 7.97 (1H,s), 7.58 (6H, m), 5.78 (2H, s), 4.13 (2H, q, J 7.2 Hz), 1.19 (3H, t, J7.2 Hz); m/e (ES⁺) 410 [MH]⁺; Anal. found: C, 66.53; H, 4.69; N, 23.71%.C₂₃H₁₉N₇O.(0.25H₂O) requires: C, 66.73; H, 4.75; N, 23.68%.

EXAMPLE 8

[0144]2,5-Diphenyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine

[0145] By reaction of the product of Example 7a) according to the methodof Example 1i), but utilizing (1-methyl-1H-[1,2,4]triazol-3-yl)methanol,the title compound was prepared. Recrystallisation fromdichloromethane/diethyl ether/isohexane afforded a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.77 (1H, s), 8.51 (1H, s), 8.23 (4H, m), 7.58 (6H,m), 5.62 (2H, s), 3.88 (3H, s); m/e (ES⁺) 396 [MH]⁺.

EXAMPLE 9

[0146]3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenyl-2-(2-thienyl)-pyrazino[2,3-d]pyridazine

[0147] a) 8-Phenyl-3-(2-thienyl)-1H-pyrazino[2,3-d]pyridazin-2-one

[0148] By an entirely analogous method to that used for Example 1h), bututilizing (2-thienyl)glyoxylic acid instead of cyclohexylglyoxylic acid,the title product was obtained. ¹H NMR (360 MHz, DMSO-d₆) δ 12.80 (1H,vbs), 9.43 (1H, s), 8.52 (1H, m), 8.01 (1H, m), 7.80 (2H, m), 7.58 (5H,m), 7.31 (1H, m); m/e (ES⁺) 307 [MH]⁺.

[0149] b)3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenyl-2-(2-thienyl)-pyrazino[2,3-d]pyridazine

[0150] By reaction of the product of Example 9a) according to the methodof Example 1i), but utilizing (2-methyl-2H-[1,2,4]triazol-3-yl)methanol(prepared as described in WO 98/04559), the title compound was prepared.Recrystallisation from dichloromethane/methanol afforded a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (1H, s), 8.33 (1H, m), 8.15 (2H, m),8.06 (1H, m), 8.00 (1H, s), 7.60 (3H, m), 7.35 (1H, m), 5.85 (2H, s),3.86 (3H, s); m/e (ES⁺) 402 [MH]⁺; Anal. found: C, 59.29; H, 3.90; N,23.86%. C₂₀H₁₅N₇OS.(0.25H₂O) requires: C, 59.17; H, 3.85; N, 24.15%.

1. A compound of formula I, or a salt or prodrug thereof:

wherein Z represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl,C₆₋₈ bicycloalkyl, aryl, C₃₋₇ heterocycloalkyl, heteroaryl ordi(C₁₋₆)alkylamino, any of which groups may be optionally substituted;R¹ represents C₃₋₇ cycloalkyl, phenyl, furyl, thienyl or pyridinyl, anyof which groups may be optionally substituted; and R² represents C₃₋₇cycloalkyl(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted.
 2. A compound as claimed inclaim 1 represented by formula IIA, and salts and prodrugs thereof:

wherein Z and R¹ are as defined in claim 1; m is 1 or 2; and R¹²represents aryl or heteroaryl, either of which groups may be optionallysubstituted.
 3. A compound as claimed in claim 2 represented by formulaIIB, and pharmaceutically acceptable salts thereof:

wherein R¹ is as defined in claim 1; Q represents the residue of acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl orthienyl ring; R³ represents hydrogen, methyl or fluoro; and R⁴represents methyl or ethyl.
 4. A compound as claimed in claim 3 whereinQ represents the residue of a cyclopropyl, cyclohexyl, phenyl, furyl orthienyl ring.
 5. A compound as claimed in any one of the precedingclaims wherein R¹ represents phenyl, fluorophenyl or difluorophenyl. 6.A compound selected from:2-cyclohexyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;2-sec-butyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;2-cyclopropyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-2-(furan-2-yl)-5-phenylpyrazino[2,3-d]pyridazine;2-tert-butyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;2-tert-butyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-5-phenylpyrazino[2,3-d]pyridazine;2,5-diphenyl-3-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine;2,5-diphenyl-3-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)pyrazino[2,3-d]pyridazine;3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-phenyl-2-(2-thienyl)-pyrazino[2,3-d]pyridazine;and salts and prodrugs thereof.
 7. A pharmaceutical compositioncomprising a compound of formula I as defined in claim 1 or apharmaceutically acceptable salt thereof or a prodrug thereof inassociation with a pharmaceutically acceptable carrier.
 8. The use of acompound of formula I as defin in claim 1 or a pharmaceuticallyacceptable salt thereof or a prodrug thereof for the manufacture of amedicament for the treatment and/or prevention of adverse neurologicalconditions.
 9. A process for the preparation of a compound of formula Ias defined in claim 1 which comprises reacting a compound of formula III(or its 2-hydroxypyrazino[2,3-d]pyridazine tautomer) with a compound offormula IV:

R²-L¹  (IV) wherein Z, R¹ and R² are as defined in claim 1, and L¹represents a suitable leaving group.
 10. A method for the treatmentand/or prevention of adverse neurological conditions, which comprisesadministering to a patient in need of such treatment an effective amountof a compound of formula I as defined in claim 1 or a pharmaceuticallyacceptable salt thereof or a prodrug thereof.